The degenerative evolution from multicellularity to unicellularity during cancer

The degenerative evolution from multicellularity to unicellularity during cancer

Theoretical reasoning suggests that human cancer may result from knocking down the genetic constraints evolved for maintenance of the metazoan multicellularity, which, however, requires a critical test. Using xenograft-based experimental evolution we characterized for the first time the full life history from initiation to metastasis of a tumor at the genomic and transcriptomic levels, and observed metastasis-driving positive selection for generally loss-of-function mutations on a set of multicellularity-related genes, which is further supported by large-scale exome data of clinical tumor samples. Subsequent expression analysis revealed mainly expression down-regulation of multicellularity-related genes, which form an evolving expression profile approaching that of embryonic stem cells, the cell type with the most characteristics of unicellular life. The theoretical conjecture predicts that genes born at the emergence of metazoan multicellularity tend to be cancer drivers, which we validated using a rigorous phylostratigraphy analysis on the birth rate of genes annotated by Cancer Gene Census. Also, the number of loss-of-function tumor suppressors often predominates over activated oncogenes in a typical tumor of human patients. These data collectively suggest that, different from typical organismal evolution in which gain of new genes is the mainstream, cancer represents a loss-of-function-driven degenerative evolution back to the unicellular ground state. This cancer evolution model may explain the enormous tumoral genetic heterogeneity in the clinic, underlie how distant-organ metastases originate in primary tumors despite distinct environmental requirements, and hold implications for designing effective cancer therapy.